Cardiovascular disease remains the most common cause of mortality. We studied the change in outcomes for anterior ST-elevation myocardial infarction (STEMI) between 1995 and 2014. Over the past 20 years, 1,658 patients presenting to our center with anterior STEMI underwent primary percutaneous coronary intervention within 12 hours of presentation. We divided these into 4 quartiles, 1995 to 1999 (n = 312), 2000 to 2004 (n = 408), 2005 to 2009 (n = 428), and 2010 to 2014 (n = 510). Across the 4 quartiles, mean age decreased (64.4, 62, 60.3, and 60 years, p <0.01). In all groups, there was a significant rise in prevalence of smoking, hypertension, and obesity. The median length of hospital stay decreased (6, 4.4, 4.2, and 3.6 days, p <0.01), as did the median door-to-balloon time (DBT) (217, 194, 135, and 38 minutes, p <0.01). Thirty-day and 1-year mortality improved over time (14.4%, 11.8%, 8.4%, and 7.8%; and 20.5%, 16.4%, 15.9%, and 13.9%) (p = 0.01 both). Also, 3-year mortality improved (25.3%, 21.6%, 21.3%, and 16.5%, p = 0.02). After adjusting for age, gender, co-morbidities, ejection fraction, clinical shock, and mitral regurgitation, shorter DBT was associated with lower long-term mortality (compared with DBT <60 minutes; 60 to 90 minutes hazard ratio [HR] 1.67, 95% confidence interval [CI] 0.93 to 3.00, p = 0.084; 90 to 120 minutes, HR 1.74, 95% CI 1.02 to 2.95, p = 0.04; >120 minutes, HR 1.91, 95% CI 1.23 to 2.96, p = 0.004). In conclusion, over the past 2 decades, long-term outcomes improved in patients presenting with anterior STEMI associated with shortening of DBT.